Rare respiratory diseases: the MUHC unique approach combining immunology and respiratory expertise for children and adults

The Research Institute of the McGill University Health Centre (RI-MUHC) is a proud member of the Genetic Disorders of Mucociliary Clearance Consortium (GDMCC), which is dedicated to advance understanding and treatment of rare genetic causes of suppurative airway disease, a condition that causes patients to have recurrent pneumonias and bronchiectasis (damaged airways). The Consortium, which is part of the Rare Disease Clinical Research Network (RDCRN), was awarded approximately $7.5 million US by the National Center for Advancing Translational Sciences (NCATS) and the National Heart Lung and Blood Institute (NHLBI) over the next 5 years to bring meaningful clinical trials to patient populations with rare lung diseases. When these patients develop an infection, the usual medical approach is to give antibiotics; however, an evaluation for the underlying cause of their condition is often not pursued, preventing optimal therapy.

“The MUHC is one of the only two Canadian sites – and the only one in Quebec – that will benefit from this prestigious NIH grant,” says Dr. Adam Shapiro, investigator in the RI-MUHC Child Health and Human Development Program and Pediatric Respirologist at the Montreal Children’s Hospital of the MUHC, as well as the MUHC site leader of this study. “Furthermore, we are the only Canadian site that combines immunology and respiratory expertise, as well as pediatric and adult expertise.”

In this grant cycle, the Consortium will identify and characterize primary immunodeficiencies, which are genetic disorders of the immune system and can often have upper and lower respiratory manifestations that resemble primary ciliary dyskinesia (PCD), and other airway diseases. PCD is a rare genetic disease of the cilia – microscopic structures that sweep the airways, ears and sinuses to keep them free from infection. It leads to chronic respiratory tract disease, left-right organ laterality defects and infertility.

Specifically, the purpose of this research study is to test patients with known or suspected (possible) PCD for genetic mutations (genes that develop differently) that cause PCD. These patients will be identified and enrolled by clinical and lab evaluation. 

“Some of these patients don’t actually have PCD, but a rare genetic immunodeficiency that causes recurrent pneumonias and bronchiectasis,” says Dr. Donald Vinh, scientist in the Infectious Diseases and Immunity in Global Health Program at the RI-MUHC, physician in Infectious Diseases and Microbiology at the MUHC, and site co-investigator for this study. “This research will allow  patients to get full genetic testing for these types of rare diseases of the lung and of their immune system. They will no longer be considered a ‘clinical mystery’,” says Dr. Vinh.

“People with PCD cannot effectively get mucus out of their lungs, which leads to many bronchial infections. But because PCD symptoms look like a number of other common lung disease, the disease often goes unnoticed and is extremely difficult to diagnose,” explains Dr. Shapiro, who has worked with the Consortium for the last 5 years pioneering the diagnostic criteria. “So far, we found 44 different genes that cause this.”

“Here at the MUHC, we have diagnosed one of the largest PCD patient populations in the world,” says Dr. Shapiro, who provides state-of-the-art diagnostic testing, with phenotype and genotype testing. “We also have one of the only machines in Canada that can perform a non-invasive test to measure a special gas coming out the nose called nasal nitric oxide, which is very low in PCD patients.” 

At the moment, most doctors don’t have the means to investigate the cause of lung disease in their patients. And that is why more and more respirologists and immunologists from all over Canada refer their patients to Dr. Shapiro when they suspect a case of PCD - in a child as well as in an adult.  When the possibility of PCD seems unlikely, Dr. Vinh checks for the presence of an immune deficiency, and vice versa. Dr. Reza Alizadehfar, a sub-investigator in this research, also bridges the gap between adult and pediatric medicine, offering immunology consultations at both the Montreal Children’s Hospital and the Montreal General Hospital of the MUHC.

“Adam, Reza, and I work in close collaboration, and we want to see all these medical orphans who come to us with these respiratory problems so we can describe their symptoms in scientific terms, and to look at the genetics of immune deficiencies,” says Dr. Vinh.

Genetics open the door to personalized medicine and the development of new gene specific targeted therapies. In addition, genetics can be used to see who is at risk in a family, and with further studies, it could lead to preventive measures being offered to newborns.

“Genetics is the way to go for all these reasons,” say the scientists, who are both Associate Professors at McGill University.
 “This is very exciting and it brings a lot of hope for our patients,” adds Dr. Shapiro. “This is real patient-oriented research. It’s research that is part of the clinical care.”

About the Genetic Disorders of Mucociliary Clearance Consortium

The Consortium consists of eight main research centres, working in close partnership with patient advocacy organizations, like the PCD Foundation, Immune Deficiency Foundation and Jeffrey Modell Foundation. In addition to Dr. Stephanie Davis and Dr. Thomas Ferkol (GDMCC Principle Investigators), other site investigators include Dr. Margaret Leigh and Dr. Michael Knowles (University of North Carolina at Chapel Hill), Dr. Scott Sagel (The Children’s Hospital Colorado), Dr. Margaret Rosenfeld (Seattle Children’s Hospital), Dr. Adam Shapiro (McGill University Health Centre, Montréal, Canada), Dr. Sharon Dell (The Hospital for Sick Children, Toronto, Canada), Dr. Carlos Milla (Stanford University Medical Center), and Dr. Kenneth Olivier (NHLBI, Bethesda, MD). 

The Genetic Disorders of Mucociliary Clearance Consortium is supported by theNCATS/NHLBI grant 2U54HL096458. 

Visit the GDMCC website at https://www.rarediseasesnetwork.org/cms/gdmcc for more details.